AU2016344537B2

AU2016344537B2 - Method for producing flutemetamol

Info

Publication number: AU2016344537B2
Application number: AU2016344537A
Authority: AU
Inventors: Tomoyuki MATSUNAMI; Yuki Okumura; Gota TONOYA
Original assignee: GE Healthcare Ltd; Nihon Medi Physics Co Ltd
Current assignee: GE Healthcare Ltd; Nihon Medi Physics Co Ltd
Priority date: 2015-10-28
Filing date: 2016-10-17
Publication date: 2020-09-17
Anticipated expiration: 2036-10-17
Also published as: US10472338B2; MX2018005046A; JP6485914B2; RU2733398C2; CN108137520A; IL258148B; AU2016344537A1; HK1249098A1; EP3368518B1; KR20180073581A; US20190055207A1; CN108137520B; WO2017071980A1; MX376470B; BR112018007545A2; CA2998985C; RU2018113741A; ES2766474T3; KR102668514B1; CA2998985A1

Abstract

Provided is a method for producing flutemetamol including the steps of: reacting a precursor compound represented by a predetermined general formula with a radioactive fluoride to obtain a

Description

METHOD FOR PRODUCING FLUTEMETAMOL FIELD OF THE INVENTION

[0001]

The present invention relates to a method for producing

flutemetamol.

BACKGROUND OF THE INVENTION

[0002]

Flutemetamol (1 8 F) Injection is an agent used for

visualizing B-amyloid beta plaques in the brain by positron

emission tomography, and is useful in diagnosis of Alzheimer

type dementia.

[00031

As a method for producing [1 8 F]flutemetamol, for example,

using a radiopharmaceutical synthesizer "FASTlab", a method of

reacting AH111907 (6-ethoxymethoxy-2-(4'-(N-formyl-N

methyl)amino-3'-nitro)phenylbenzothiazole) with a radioactive

fluoride to replace the nitro group of AH111907 by 18F, then

converting AH111907 residue into a less fat-soluble substance by

a strong base, removing protective groups of the hydroxy group

and amino group of the 18 F substitution product of AH111907 (6

ethoxymethoxy-2-(4'-(N-formyl-N-methyl)amino-3'

[1 8F]fluoro)phenylbenzothiazole), then performing purification

using a solid phase extraction cartridge is known

(W02011/044406).

[00051

However, the yield of [1 8 F]flutemetamol is low in the method

described in W02011/044406, thus, delivery to a wide range by

mass production has been difficult. Therefore, in order to supply [1 8 F]flutemetamol formulation to more patients, it has been required to improve productivity.

SUMMARY OF THE INVENTION

[00061

The present invention has been made in consideration of the

above situation, and an object of the present invention is to

improve productivity of [1 8 F]flutemetamol.

[0007]

According to an aspect of the present invention, there is

provided a method for producing flutemetamol including the steps

of:

(a) reacting a compound represented by the following general

formula (1) with a radioactive fluoride to obtain a compound

represented by the following general formula (2);

(b) allowing a strong base to act on the reaction mixture of the

step (a) containing the compound represented by the following

general formula (1) and the compound represented by the

following general formula (2);

(c) after the step (b), purifying the compound represented by

the following general formula (2) using a reverse phase solid

phase extraction cartridge; and

(d) removing a protective group to obtain [1 8 F]flutemetamol.

[00081

R0 -- R2

| / (1)

[00091 wherein R, is a protective group of hydroxy, and C(O)R 2 represents a protective group of amino.

[0010]

[0011]

wherein R, and R 2 have the same meaning as in the compound

represented by the general formula (1).

[0012]

According to the present invention, productivity of

[1 8F]flutemetamol can be improved.

DETAILED DESCRIPTION

[0013]

The term "alkyl" herein used alone or as a part of the

other group denotes a saturated or branched saturated

hydrocarbon group such as methyl, ethyl, propyl, isopropyl,

butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl.

[0014]

Further, the term "haloalkyl" herein used alone or as a

part of the other group denotes one in which one or more

hydrogen of alkyl is replaced by fluorine, chlorine, bromine, or

iodine.

[0015]

Moreover, the term "alkoxy" herein used alone or as a part

of the other group denotes a saturated or branched saturated

hydrocarbon group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentoxy, or n-hexyloxy.

[0016]

Further, the term "aryl" herein used alone or as a part of

the other group denotes a monocyclic or condensed ring aromatic

hydrocarbon such as phenyl or naphthyl.

[0017]

(a) 'IF labeling step

In the 18 F labeling step, the compound represented by the

general formula (1) (hereinafter, also referred to as "labeling

precursor compound") is reacted with a radioactive fluoride to

obtain a compound represented by the following general formula

8 (2) (hereinafter, also referred to as "1 F labeling intermediate

compound").

[0018]

As the protective group of hydroxy of R1 , those described

in Greene's Protective Groups in Organic Synthesis (published by

Wiley-Interscience, 4th edition, issued on October 30, 2006) can

be used. The group represented by ORi is preferably an

alkoxymethoxy group having 1 to 6 carbon atoms, and examples

include an ethoxymethoxy group and a methoxymethoxy group.

[0019]

R 2 is selected from hydrogen, alkyls having 1 to 10 carbon

atoms, haloalkyls having 1 to 10 carbon atoms, aryls having 6 to

14 carbon atoms, arylalkyls having 6 to 14 carbon atoms, and

(CH 2 CH 2 0)p-CH3 wherein p is an integer of 1 to 10. R 2 is

preferably hydrogen or an alkyl having 1 to 10 carbon atoms,

more preferably hydrogen or methyl, and further preferably

hydrogen.

[0020]

The labeling precursor compound can be synthesized, for

example, using a method described in W02007/020400. A preferred

example of the labeling precursor compound is 6-ethoxymethoxy-2

(4'-(N-formyl-N-methyl)amino-3'-nitro)phenylbenzothiazole

(AH111907), and an example of the synthesis method thereof is

described in Example 1 of W02007/020400.

[0021]

The radioactive fluoride can be obtained by adding a

cationic counter ion to an aqueous solution containing a

[1 8F]fluoride ion obtained from [180]water by 180(p,n)l 8F nuclear

reaction to remove water. The cationic counter ion is preferably

one having sufficient solubility in an anhydrous reaction

solvent, so that the solubility of the [1 8F]fluoride ion can be

maintained. Examples include tetraalkyl ammonium and alkali

metal ions (sodium ion, potassium ion, cesium ion, rubidium ion)

forming a complex with a phase transfer catalyst (for example,

4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane

(trade name: Kryptofix 2.2.2)), and tetrabutyl ammonium is

preferred. [1 8 F]Tetrabutyl ammonium fluoride can be prepared, for

example, by passing the [1 8 F]fluoride ion-containing [1 8 0]water

obtained by 180(p,n)l 8F nuclear reaction through an anion

exchange resin to adsorb the [1 8 F]fluoride ion to the anion

exchange resin, eluting it with an aqueous solution of

tetrabutylammonium hydrogen carbonate, and forming an azeotropic

mixture with acetonitrile.

[0022]

The 18 F labeling step may be carried out in an appropriate

solvent. As the solvent, as acetonitrile, dimethylformamide,

dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, dioxane,

1,2-dimethoxyethane, sulfolane, N-methylpyrrolidone, an

imidazolium derivative such as 1-butyl-3-methylimidazolium

hexafluorophosphate, a pyridinium derivative such as 1-butyl-4

methylpyridinium hexafluoroborate, a phosphonium compound, or an

ionic liquid such as a tetraalkylammonium compound can be used,

and dimethyl sulfoxide is preferred.

[0023]

The 18 F labeling step can be, for example, carried out at

the range of 15 to 1800C, preferably 80 to 1500C, and more

preferably 120 to 1400C, and carried out further preferably at

around 130°C.

[0024]

(b) Precursor decomposition step

In the precursor decomposition step, a strong base is

allowed to act on the reaction mixture in the 18F labeling step

containing the labeling precursor compound and the 18F labeling

intermediate compound. Thereby, the labeling precursor compound

residue contained in the reaction mixture in the 18 F labeling

step is converted into a highly polar compound. As the highly

polar compound, those shown in Fig. 1 of W02011/044406 can be

considered. In the precursor decomposition step, the 18 F labeling

intermediate compound remains without reacting with a strong

base.

[0025]

The strong base includes alkali metal alkoxides, alkali

metal hydroxides and the like, and sodium methoxide, sodium

ethoxide, sodium hydroxide, potassium hydroxide, sodium hydride

or methylmercaptan sodium is preferably used. The strong base is

more preferably sodium methoxide or sodium ethoxide, and further preferably sodium methoxide.

[0026]

The precursor decomposition step is preferably carried out

in the presence of a solvent. The solvent includes alkyl

alcohols, and methanol is preferred.

[0027]

The precursor decomposition step can be, for example,

carried out at the range of 15 to 1800C, preferably 80 to 150°C,

and more preferably 120 to 1400C, and carried out further

preferably at around 130°C.

[0028]

(c) First purification step

In the first purification step, after the precursor

decomposition step, the 18 F labeling intermediate compound is

purified using a reverse phase solid phase extraction cartridge.

Thereby, the 18 F labeling intermediate compound, and the highly

polar compound obtained in the precursor decomposition step are

separated.

[0029]

As the reverse phase solid phase extraction cartridge, one

using a filler in which a silyl group is modified with alkyl

having preferably 8 or more carbon atoms and more preferably 18

or more carbon atoms is used, and a solid phase extraction

cartridge packed with triacontyl silylated silica gel in which a

silyl group is modified with 30 carbon atoms is further

preferably used. Such reverse phase solid phase extraction

cartridge is commercially available, for example, from Macherey

Nagel. The reverse phase solid phase extraction cartridge is

preferably conditioned with acetonitrile and water before use.

[00301

Purification of the 18 F labeling intermediate compound using

a reverse phase solid phase extraction cartridge is not

particularly limited as long as it is carried out using a

technique of normal solid phase extraction method. An example

will be explained below.

[0031]

First, the 18F labeling intermediate compound through the

precursor decomposition step is held in a reverse phase solid

phase extraction cartridge [(c-1) holding step]. Preferably,

after the precursor decomposition step, the reaction mixture

containing the 18 F labeling intermediate compound and the highly

polar compound described above is diluted by adding water, and

loaded on a reverse phase solid phase extraction cartridge.

[0032]

Subsequently, the reverse phase solid phase extraction

cartridge is washed with a mixture liquid of water and one or

more organic solvents selected from a group consisting of

acetonitrile, tetrahydrofuran and alkyl alcohols having 1 to 3

carbon atoms [(c-2) washing step]. The solvent used for washing

is preferably a mixture liquid of water and acetonitrile, and as

the mixing ratio thereof, for example, the content of

acetonitrile can be 35 to 45% by volume, and preferably 39.5 to

40.5% by volume of the entire mixture liquid. The temperature of

the reverse phase solid phase extraction cartridge is preferably

in the range of 19 to 340C and more preferably in the range of

20 to 30°C. This washing step may be repeated for a plurality of

times. Thereby, the highly polar compound described above can be

eluted from the reverse phase solid phase extraction cartridge, while holding the 'IF labeling intermediate compound in a reverse phase solid phase extraction cartridge.

[00331

Thereafter, the 18F labeling intermediate compound is eluted

with an alkyl alcohol having 1 to 3 carbon atoms from the

reverse phase solid phase extraction cartridge [(c-3) elution

step]. The alkyl alcohol having 1 to 3 carbon atoms includes

methanol, ethanol, 1-propanol, and 2-propanol, and ethanol is

more preferable from the viewpoint of safety. At this time,

nitrogen gas may be flown from the inlet port of the reverse

phase solid phase extraction cartridge or sucked from the

discharge port. The obtained eluate can be used in the next step

as it is or after concentrating the solvent under heating or

reduced pressure.

[0034]

(d) Deprotection step

In the deprotection step, protective groups of the hydroxy

group and amino group are each removed to obtain

[1 8F]flutemetamol.

[00351

The deprotection step may be carried out in accordance with

the description of Greene's Protective Groups in Organic

Synthesis (published by Wiley-Interscience, 4th edition, issued

on October 30, 2006), and it is preferred to carry out acid

hydrolysis using an organic acid or inorganic acid. As the acid,

an inorganic acid such as sulfuric acid, hydrochloric acid,

phosphoric acid or hydrobromic acid is preferably used, and

hydrochloric acid is more preferably used.

[00361

The deprotection step can be carried out in the presence of

water, an organic solvent such as an alkyl alcohol having 1 to 4

carbon atoms or acetonitrile or a mixture liquid thereof, and it

is preferred to add an acid to an ethanol eluate obtained by the

elution step of the first purification step and then carry out

the deprotection step.

[0037]

The deprotection step is preferably carried out at 1000C or

more.

[00381

(e) Second purification step

In the second purification step, after the deprotection

step, the [1 8F]flutemetamol is purified using a reverse phase

solid phase extraction cartridge.

[00391

As the type of the reverse phase solid phase extraction

cartridge used in the second purification step, one that can be

used in the first purification step can be used, and a solid

phase extraction cartridge packed with triacontyl silylated

silica gel in which a silyl group is modified with 30 carbon

atoms is preferably used.

[0040]

Purification of the [1 8F]flutemetamol using a reverse phase

solid phase extraction cartridge is not particularly limited as

long as it is carried out using a technique of normal solid

phase extraction method. An example will be explained below.

[0041]

First, the [1 8 F]flutemetamol through the deprotection step

is held in a reverse phase solid phase extraction cartridge [(e

1) holding step]. Preferably, after the deprotection step, the

crude product of [1 8 F]flutemetamol is diluted by adding water, so

that the content of the organic solvent taken from the previous

step (for example, ethanol taken from the first purification

step) is 50% by volume or less, and loaded on a reverse phase

solid phase extraction cartridge.

[0042]

Subsequently, the reverse phase solid phase extraction

cartridge is washed with water or a mixture liquid of water and

one or more organic solvents selected from a group consisting of

acetonitrile, tetrahydrofuran and alkyl alcohols having 1 to 3

carbon atoms [(e-2) washing step]. The solvent used for washing

is preferably a mixture liquid of water and acetonitrile, and as

the mixing ratio thereof, for example, the content of

acetonitrile can be 35 to 45% by volume, and preferably 39.5 to

40.5% by volume of the entire mixture liquid. The temperature of

the reverse phase solid phase extraction cartridge is preferably

in the range of 19 to 340C and more preferably in the range of

20 to 30°C. This washing step may be repeated for a plurality of

times, and at this time, the reverse phase solid phase

extraction cartridge is preferably washed with water. Thereby,

unnecessary solvent and the deprotecting reagent can be removed,

while holding the [1 8 F]flutemetamol in the reverse phase solid

phase extraction cartridge.

[0043]

Thereafter, the [1 8 F]flutemetamol is eluted with ethanol

from the reverse phase solid phase extraction cartridge [(e-3)

elution step]. Thereafter, water may be further passed through

and combined with the eluate. Furthermore, nitrogen gas may be flown from the inlet port of the reverse phase solid phase extraction cartridge or sucked from the discharge port.

[0044]

(f) Third purification step

In the third purification step, after the second

purification step, the [1 8 F]flutemetamol is purified using a

hydrophilic interaction (HILIC) solid phase extraction

cartridge.

[0045]

As the HILIC solid phase extraction cartridge, for example,

one packed with silica gel, or silica gel in which a highly

polar functional group such as amino, amide, cyano, diol, a

polysuccinimide derivative, zwitterion or cyclodextrin is

introduced can be used. Here, a silica gel-based amino solid

phase is preferable, and one packed with aminopropylated silica

gel is more preferable. Thereby, impurities can be captured with

the HILIC solid phase extraction cartridge, while allowing the

[1 8F]flutemetamol to pass through. Such HILIC solid phase

extraction cartridge is commercially available, for example,

from Waters, Agilent Technologies, and the like. The HILIC solid

phase extraction cartridge is preferably conditioned by passing

acetonitrile or ethanol before use, followed by flowing nitrogen

to be dried.

[0046]

Subsequently, the eluate obtained in the second

purification step is directly allowed to pass through the HILIC

solid phase extraction cartridge. Thereafter, water may be

passed through, and the eluate may be combined. Furthermore,

nitrogen gas may be flown from the inlet port of the HILIC solid phase extraction cartridge or sucked from the discharge port.

[0047]

The obtained eluate may contain a pharmaceutically

acceptable carrier, diluent, emulsion, excipient, extender,

dispersant, buffer, preservative, solubilizer, antiseptic,

colorant, stabilizer, and the like, so as to have a form

suitable for administration of [' 8F]flutemetamol to a living

body, preferably a form of injection. The obtained

[1 8F]flutemetamol-containing solution is desirably filtered with

a membrane filter.

[0048]

The formulation example of [1 8F]flutemetamol is, for

example, disclosed in W02009/027452.

[0049]

According to the method of the present invention described

above, the first purification step conventionally carried out

after the deprotection step is carried out after the 18 F labeling

step and before the deprotection step. When the first

purification step is carried out after the deprotection step,

many impurities containing the highly polar compound derived

from the labeling precursor compound are present, thus the loss

of [1 8F]flutemetamol increases with the removal of impurities. On

the other hand, the first purification step is carried out

before the deprotection step, whereby the highly polar compound

derived from the labeling precursor compound can be removed

before the deprotection step. Thereby, the 18 F labeling

intermediate compound can be purified while preventing the loss

of the 18 F labeling intermediate compound, that is an

intermediate compound of the [1 8F]flutemetamol, thus

['8F]flutemetamol can be obtained in a higher yield than a

conventional one and with a quality equivalent to a conventional

one. Therefore, according to the present invention, productivity

8 of [' F]flutemetamol can be improved.

EXAMPLES

[00501

Hereinafter, the present invention will be further

preferably described in detail with reference to the examples,

but the present invention is not limited to the content of the

examples. Here, as the reagent and column member used in the

examples, a component of a radiopharmaceutical synthesizer

FASTlab (for synthesis of flutemetamol) manufactured by GE

Healthcare or a component equivalent to the same was used.

[0051]

Examples 1 to 3

(a) 'F labeling step

[1 8 F]Fluoride ion-containing [ 8 ]water obtained by proton

8 irradiation of [ ]water using a cyclotron was passed through an

anion-exchange column, and the [1 8F]fluoride ion was adsorbed and

collected. Subsequently, the column was washed with water (3

mL), then eluted using a 0.15 mol/L aqueous solution of

tetrabutylammonium hydrogen carbonate (0.35 mL) and acetonitrile

(1 mL), and the obtained eluate was evaporated. Thereto was

added a dimethyl sulfoxide solution (1 mL) of 6-ethoxymethoxy-2

(4'-(N-formyl-N-methyl)amino-3'-nitro)phenylbenzothiazole

(AH111907) (75 pmol), and the mixture was heated at 1300C for 15

minutes, then cooled.

(b) Precursor decomposition step

A methanol solution (11% (w/w), 1 mL) of sodium methoxide

was added to the reaction liquid after cooling in the step (a),

and the mixture was heated at 1300C for 5 minutes, and cooled.

(c) First purification step

Water (2 mL) was added to the reaction liquid after cooling

in the step (b), and the mixture was passed through a triacontyl

silylated silica gel (C30) column to hold the 18 F labeling

intermediate compound. Furthermore, washing was carried out by

passing a 40% (v/v) aqueous acetonitrile solution (6 mL) through

the C30 column via a reaction vessel, then washing was again

carried out by directly passing a 40% (v/v) aqueous acetonitrile

solution (6 mL) through the C30 column. Ethanol (2 mL) was

passed through this C30 column to collect an eluate.

(d) Deprotection step

A 4 mol/L hydrochloric acid (2.0 mL) was added to the

eluate collected in the step (c), and the mixture was heated at

1250C for 5 minutes to obtain an unpurified [1 8 F]flutemetamol

solution.

(e) Second purification step

The unpurified [1 8F]flutemetamol solution obtained in the

step (d) was cooled, then water (10 mL) was added thereto, and

the mixture was passed through an unused C30 column different

from the one used in the step (b) to hold the [1 8 F]flutemetamol

in the C30 column. Washing was carried out by passing a 40%

(v/v) aqueous acetonitrile solution (6 mL) through the C30

column, then washing was carried out by passing water (6 mL).

The [1 8 F]flutemetamol was eluted with ethanol (3.5 mL) from the

C30 column.

(f) Third purification step

The eluate in the step (e) was passed through a column (NH2

column) packed with aminopropylated silica gel. Washing was

carried out by passing water (9.3 mL) through the C30 column

used in the step (e) and the NH 2 column, in this order, and each

eluate was collected in a vessel to which a 18.8 mmol/L

phosphoric acid buffer (37.2 mL) containing 0.7% (w/v)

polysorbate 80 and 1.2% (w/v) sodium chloride were added.

[0052]

Comparative Examples 1 and 2

The steps (a) and (b) of Examples 1 to 3 were carried out,

and the following steps were carried out.

(c') Deprotection step

A 4 mol/L hydrochloric acid (0.6 mL) was added to the

reaction liquid obtained in the step (b), and the mixture was

heated at 1250C for 5 minutes to obtain an unpurified

[1 8F]flutemetamol solution.

(d') First purification step

The unpurified [1 8F]flutemetamol solution obtained in the

step (c') was cooled, then water (2 mL) was added thereto, and

the mixture was passed through a C30 column to hold the

[1 8F]flutemetamol. Furthermore, washing was carried out by

passing a 40% (v/v) aqueous acetonitrile solution (12 mL)

through the C30 column via a reaction vessel, then washing was

carried out by passing water (5 mL) through the C30 column.

Acetonitrile (2 mL) was passed through this C30 column to

collect an eluate.

(e') Second purification step

The eluate obtained in the step (d') was purified by

passing through a NH 2 column, then acetonitrile solution (1 mL) was further passed through the NH 2 column, and these solutions were mixed.

(f') Third purification step

Water (5 mL) was added to the solution obtained in the step

(e'), and passed through an unused C30 column different from the

one used in the step (d') to hold the [1 8 F]flutemetamol in the

C30 column, then washing was carried out by passing water (4 mL)

through the C30 column three times. Ethanol (3.5 mL) was passed

through the C30 column, and water (9.3 mL) was passed through

the C30 column. Each eluate was collected in a vessel to which

a 18.8 mmol/L phosphoric acid buffer (37.2 mL) containing 0.7%

(w/v) polysorbate 80 and 1.2% (w/v) sodium chloride were added.

[00531

The results of Examples 1 to 3 and Comparative Examples 1

and 2 are shown in Table 1. In Table 1, the "radioactivity

amount (MBq)" is a radioactivity amount of [1 8 F]fluoride ion at

the start of synthesis, used in each example and comparative

example, the "synthesis time (minute)" is a time required to

perform each example and comparative example, and the

"radiochemical yield (%)" is a radiochemical yield of

[1 8F]flutemetamol based on the radioactivity amount of

[1 8F]fluoride ion after attenuation correction at the start of

synthesis, the "radiochemical purity (%)" is a radiochemical

purity of [1 8F]flutemetamol, and the "total amount of

nonradioactive impurities (pg/mL)" is a concentration of

nonradioactive impurities in the obtained [1 8 F]flutemetamol

solution.

The radiochemical purity of [1 8 F]flutemetamol and the

concentration of nonradioactive impurities were analyzed by the methods shown below.

[0054]

1. Analysis of radiochemical purity of ['8F] flutemetamol

The analysis was conducted by TLC. The conditions are as

follows.

TLC plate: Silica Gel 60 F 2 5 4 (manufactured by Merck)

Mobile phase: Ethyl acetate/diethylamine = 100/1

Measuring device: Rita Star (manufactured by raytest)

[00551

2. Analysis of concentration of nonradioactive impurities in the

[1 8 F]flutemetamol solution

The analysis was conducted by HPLC equipped with an UV

detector. The conditions are as follows.

Column: Luna C18(2) (manufactured by Phenomenex, size: 4.6

x 150mm, 3 pm)

Mobile phase: A 20 mmoL ammonium acetate buffer (pH

6.0)/acetonitrile = 62/38 - 40/10 (0 - 9 minutes), 40/10 - 10/90

(9 - 10 minutes), 10/90 (10 - 20 minutes), 10/90 - 62/38 (20

20.5 minutes), 62/38 (20.5 - 30 minutes)

Flow rate: 1.0 mL/minute

Detector: Ultraviolet visible light absorption photometer

(detection wavelength: 330 nm)

[00561

Table 1 Radioactivity Synthesis Radiochemical Radiochemical Total amount (MBq) time yield(%) purity(%) amount of (minute) nonradioa ctive impurities (pg/mL) Example 1 1570 56 52.9 99.6 2.62 Example 2 1559 54 56.0 99.6 1.98 Example 3 1121 54 55.5 99.0 1.66

H:\Interwoven\NRPortbl\DCC\SXD\2061,56241.doex-9/1/2020

Comparative 1508 73 41.0 94.9 1.82 Example Comparative 1054 66 30.3 92.5 0.69 Example2

[0057] As shown in Table 1, the radiochemical yield of

[1 8F]flutemetamol was improved by the methods of Examples 1 to 3, and the synthesis time could be shortened. Further, the radiochemical purity was improved, and the marked increase in the total amount of impurities was not found. Therefore, it was shown that, according to the present invention, [1 8 F]flutemetamol having the same quality can be obtained while improving the productivity more than a conventional one.

[0058] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0059] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

H:\Interwoven\NRPortbl\DCC\SXD\206156241.docx-9/1/2020 The claims defining the invention are as follows:

1. A method for producing flutemetamol comprising the steps

of:

(a) reacting a compound represented by the following

general formula (1) with a radioactive fluoride to produce a

compound represented by the following general formula (2);

(b) allowing a strong base to act on the reaction

mixture of the step (a) containing the compound represented

by the general formula (1) and the compound represented by

the general formula (2);

(c) after the step (b), purifying the compound

represented by the general formula (2) using a reverse phase

solid phase extraction cartridge; and

(d) removing a protective group to produce

[1 8 F]flutemetamol. NO2 O

R 10 g R2

wherein Ri is a protective group of hydroxy, and C(O)R 2

represents a protective group of amino. IS 0

R 10 S R2

H:\Interwoven\NRPortbl\DCC\SXD\2061,56241.doex-9/1/2020

wherein Ri and R 2 have the same meaning as in the compound

represented by the general formula (1).

2. The method for producing flutemetamol according to claim

1, wherein the step (c) includes the steps of:

(c-1) holding the compound represented by the general

formula (2) in a reverse phase solid phase extraction

cartridge;

(c-2) washing the reverse phase solid phase extraction

cartridge with a mixture liquid of one or more organic

solvents selected from water and a group consisting of

acetonitrile, tetrahydrofuran and alkyl alcohols having 1 to

3 carbon atoms; and

(c-3) eluting the compound represented by the general

formula (2) with an alkyl alcohol having 1 to 3 carbon atoms

from the reverse phase solid phase extraction cartridge.

3. The method for producing flutemetamol according to claim

2, wherein, in the step (c-2), the reverse phase solid phase

extraction cartridge is washed with a mixture liquid of

water and acetonitrile.

4. The method for producing flutemetamol according to claim

2 or 3, wherein, in the step (c-3), the alkyl alcohol having

1 to 3 carbon atoms is ethanol.

H:\Interwoven\NRPortbl\DCC\SXD\2061,56241.doex-9/1/2020

5. The method for producing flutemetamol according to any

one of claims 1 to 4, wherein the reverse phase solid phase

extraction cartridge in the step (c) is one packed with

triacontyl silylated silica gel.

6. The method for producing flutemetamol according to any

one of claims 1 to 5, further comprising the steps of:

(e) after the step (d), purifying the [1 8F]flutemetamol

using a reverse phase solid phase extraction cartridge; and

(f) after the step (e), purifying the [1 8F]flutemetamol

using a hydrophilic interaction solid phase extraction

cartridge.

7. The method for producing flutemetamol according to claim

6, wherein the reverse phase solid phase extraction

cartridge in the step (e) is one packed with triacontyl

silylated silica gel.

8. The method for producing flutemetamol according to claim

6 or 7, wherein the hydrophilic interaction solid phase

extraction cartridge in the step (f) is one packed with

aminopropylated silica gel.